Among cardiovascular drugs, Angiotensin II receptor antagonists like Losartan potassium are prominently used as an active ingredient in the management of hypertension. Losartan potassium plays an effective role in patients having difficulty in tolerating ACE inhibitors. The chemical name of Losartan potassium is 2-n-Butyl-4-Chloro-1-[((2′-tetrazol-5-yl)-1,1′-bisphenyl-4-yl)methyl]-imidazole-5-methanol potassium.
It is known in the art to synthesize Losartan potassium from the acid form of Losartan. Losartan potassium (shown as the compound of Formula (I) below) is known in the art is synthesized by reacting its acid (shown as the compound of formula (II) below) with KOH. The intermediate acid Formula (II) in turn is synthesized by detritylation of 2-n-butyl-4-chloro-5-hydroxymethyl-1-[((2′-triphenylmethyltetrazole-5-yl)biphenyl-4-yl) methyl] imidazole (shown as the compound of Formula (III) below)
The synthesis of Trityl Losartan (the reactant of Formula (III) below) is known in the art. See 34 J. MED. CHEM. 2525-27 (1991); 59 J. ORG. CHEM. 6391-94 (1994); U.S. Pat. No. 5,138,069. Trityl Losartan (and the Losartan acid/free Losartan) and may alternatively be prepared using the reactions and techniques described in U.S. Pat. No. 5,138,069 and patent application number W093/10106.

The preparation from Trityl Losartan (the reactant of Formula (III) of Losartan acid (II) by acid-catalyzed cleavage of trityl group from Trityl Losartan (III) is disclosed in U.S. Pat. No. 5,281,603. Another method disclosed to prepare Losartan acid from trityl Losartan is disclosed in U.S. Pat. No. 5,281,604. In this process Trityl Losartan (III) is refluxed in a mixture of methanol and tetrahydrofuran in presence of catalytic acid like hydrochloric acid for 18 hours to get Losartan acid (II).
Patent application number WO98/18787 describes a method, which also starts with a solution of Losartan Potassium (I) in aqueous isopropyl alcohol and is heated to distill out water-isopropyl alcohol mixture to lower the water content to 2.6%. Further excessive seeding is carried out with slurry of Losartan Potassium (I) in cyclohexane until the seed remains undissolved. The Precipitation of the product is then achieved by continuous distillation of ternary azeotrope with simultaneous addition of cyclohexane to the reaction mass. This azeotrope distillation is carried out until moisture level decreases to about 0.2 to 0.11%. The crystallized product thus obtained is filtered.
The present invention avoids the use of stringent azeotropic distillation of water from the reaction mass to precipitate Losartan potassium. Also it avoids the use of antisolvents for the removal of water or for the precipitation of Losartan poatassium as taught by the prior art.
Similarly, in patent application number W001/81336, Richter Gedeon describes treatment of Trityl Losartan (III) with potassium hydroxide in primary alcohols and crystallization of the product (I) from methanol with the help of anti solvents such as dipolar aprotic solvent (acetonitrille), aprotic solvent (straight or branded chain or cyclic aliphatic hydrocarbons) or a protic solvent (sec. butanol).
The Richter Gedeon approach was found to be easy and superior to the existing methods, however was found to suffer from various drawbacks as summarized below:                a) The product obtained does not pass desired solubility in various solvents. To make the product improve in quality, it needs an extra purification as per the Richter Gedeon application.        b) Purification step in the process, the resultant purity and the yields thereof, depends on very precise ratios of solvent mixture (e.g. methanol, cyclohexane or acetonitrile).        c) High volume of solvents and that too in very precise combination in purification which leads to capacity reduction of plant production/facilities.        d) Recovery and recyclability of the solvents (methanol and anti solvents) from its mixture is difficult and needs careful purification by distillation to get recyclable solvents, with very little value addition. The non-recovery option, on the other hand, leads to high pollution load.        
Patent application number WO 02/094816, discloses use of acetone, ethyl acetate, acetonitrile and toluene as anti-solvents and has similar problems of recovery and reuse of solvents and high cost of production. Since isolation of the product is simply by precipitation using anti solvents, the product needs further purification to pass the required tests, in this case also.
The art not only teaches the need for purifying the resulting Losartan potassium (I), but also various methods to purify it. For example U.S. Pat. No. 5,608,075 discloses two polymorphic forms of Losartan Potassium, which are Form I and form II. Their method of preparation and characterization by X-ray powder diffraction pattern, DSC thermograms, FT-IR spectra, Raman spectra and C13 NMR (solid state) spectra were also given. The disclosed procedure for polymorphic Form I is the addition of aqueous solution of (I) to a refluxing mixture of cyclohexane and isopropyl alcohol followed by azeotropically distilling out cyclohexane/isopropyl alcohol/water ternary azeotrope at 64° C. while the Form I crystallizes out at 69° C.
Our unpublished U.S. patent application Ser. No. 60/468,208 having priority from Indian patent application serial No. 335/MUM/2003, filed on 03 Apr. 2003, addresses these problems by the use of potassium tertiary butoxide in alcoholic solvents for the detritylation and simultaneous formation of Losartan potassium. Moreover the invention discloses the isolation in a single solvent and the easy removal of triphenyl methyl methyl ether which gives high quality Losartan potassium after normal workup. The Losartan potassium produced by this process is found identical with the crystal structure set for polymorph Form I as complied with X-ray diffraction studies, Infrared Spectroscopy and Differential Scanning Calorimeter.
However it was desired to develop a process which can be more operator friendly. In our earlier patent application potassium tertiary butoxide in powder form is used, which has its disadvantages in handling on large scale in an inert nitrogen atmospheric condition. This has led us to improve the process as per the present invention. The present invention is intended to solve the problems associated with the handling of potassium tertiary butoxide in powder form. Further to that it is also of interest to substitute potassium tertiary butoxide by other reagents and to obtain specific polymorphic Form I of Losartan potassium.